N-methyl-D-aspartate receptors (NMDARs) are responsible for the slow component of excitatory synaptic transmission in response to co-agonist binding of glutamate and glycine. The structural view of the receptors is that they are hetero-tetrameric receptors composed of two NR1 subunits and two NR2(A-D) subunits. The differential expression patterns associated with each particular NR2 subunit type present pharmacological rationale for intervention in diseases such as Parkinson's, schizophrenia, and ischemic cell death. We have identified several distinct classes of molecules that are selective against the NR2C/NR2D receptor subtypes through a medium-throughput screening endeavor. Preliminary data suggest an overlapping binding site for two distinct classes of molecules within the S2 region of the receptor may be responsible for the non- competitive, voltage independent antagonism observed with two of the classes that have been discovered. In order to test this hypothesis, we are proposing to use chimeric receptors, computer assisted modeling, and synthetic chemistry in an effort to develop potent and selective small molecules that will allow for description of the novel binding site, as well as a pharmacophore description of the small molecules. These studies will provide first in class subunit-selective pharmacological tools that will aid in furthering our understanding of the physiological and patho-physiological roles played by different NMDA receptors.